Multiple lines of evidence support a key role for abnormal synaptic connectivity in schizophrenia, but the molecular mechanisms underlying its pathogenesis are not known. Understanding these mechanisms may allow us to identify new targets for therapeutic intervention, especially early in the course of illness. The application wil focus on dendritic spines as cellular substrates of brain connectivity, because the majority of excitatory synapses are located on spines, and reduced spine density has been extensively documented in schizophrenia. Mounting evidence indicating that known schizophrenia susceptibility genes regulate spines and that regulators of spine plasticity are implicated in schizophrenia, strongly support the model that perturbations in the molecular network underlying spine plasticity are critically involved in the pathogenesis of schizophrenia. However, the mechanisms through which genetic alterations in this network underlie specific neurobiological phenotypes related to schizophrenia are not known. Recent data indicates that rare variants (including amino acid mutations) cumulatively account for a significant fraction of the missing heritability in schizophrenia, and cluster in gene networks that control synapses. Because a large fraction of such mutations are estimated to impair protein function, many are expected to cause brain circuit alterations. Thus, we propose that by identifying, testing for association, and characterizing rare variants enriched in schizophrenia, we will provide critical new insights into disease pathogenesis, because such mutations provide detailed knowledge about the affected molecular and cellular functions. Based on our preliminary data, we hypothesize that rare coding variants in genes that control dendritic spine plasticity, cumulativel enriched in subjects with schizophrenia, disrupt cortical connectivity and impact neuromorphological and cognitive measures in carriers. Using a multidisciplinary translational approach that combines human genetics, molecular and electrophysiological studies in cellular models, functional validation in mice, and cognitive assessment and structural brain imaging in patients, we will pursue these specific aims: 1) To assess the cellular impact of mutations in spine plasticity genes identified in schizophrenia subjects. 2) To determine the impact of mutations in spine plasticity genes on glutamatergic synaptic transmission. 3) To determine the impact of mutations in spine plasticity genes on cortical ultrastructure and functional connectivit in mice. 4) To assess the relationships between mutations in spine plasticity genes and phenotypic measures in patients. PUBLIC HEALTH RELEVANCE: Using a multidisciplinary and integrated translational approach we will test the hypothesis that rare protein coding mutations in genes that control dendritic spine plasticity in the cerebral cortex, which occur in subjects with schizophrenia, disrupt synapse structure and function within frontal cortical microcircuits, and affect specific neuromorphometric and cognitive measures in carriers. Data generated will provide new mechanistic insights into pathways that underlie abnormal brain connectivity in schizophrenia that will allow us to identify therapeutic targets.